Illegal Drugs and Drug Dependence 19
19.1 Epidemiological and Social Data 391 19.2 Cannabis 392
19.3 Hallucinogens and Entactogens 392 19.3.1 Mescaline 393
19.3.2 Lysergic Acid Diethylamide (LSD) 393 19.3.3 Amphetamine Substitutes 393 19.3.3.1 MDMA
(3,4-methylenedioxmethamphetamine) 393 19.3.3.2 MDEA
(3,4-methylenedioxyethamphetamine) 394 19.3.4 Other Agents 394
19.4 Narcotics: Opium and Opioids 394 19.4.1 Basic Principles 394
19.4.1.1 Epidemiology 394 19.4.1.2 Pathophysiology 395 19.4.1.3 Neuropathology 395 19.4.2 Morphine 397 19.4.3 Heroin 397 19.4.4 Codeine 397
19.4.5 Dihydrocodeine (DHC) 398 19.4.6 Methadone 398
19.4.7 Other Narcotic Agents 398
19.5 Stimulants 398 19.5.1 Cocaine 398
19.5.2 Cocaine Freebase: Crack 399 19.5.3 Amphetamine
and Methamphetamine (Speed) 399 19.5.4 Caffeine 400
19.5.5 Ephedrine 400 19.5.6 Khat 400
Bibliography 401
References 401
19.1
Epidemiological and Social Data
Alcoholism and the dependency on drugs are “dis- eases” as any others. In addition to acute and chronic alcohol intoxication, the most common form of le- thal poisoning encountered in the forensic labora- tory is acute intoxication caused by illicit drugs.
Consumption of these drugs is increasing and poses major social, psychological, medical, and forensic problems both in the United States and in Western Europe. The increasing number of deaths among young and chronic addicts is of particular concern and has caused much public debate. Associated with the rise in consumption is an increase in prostitu- tion and in the number of crimes against property and violent crimes committed by addicts to obtain money to finance their habits.
Drugs of abuse are able to elicit compulsive drug- seeking behaviors upon repeated administration, which ultimately leads to the phenomenon of ad- diction. Evidence indicates that the susceptibility to develop addiction is influenced by sources of rein- forcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. Addiction is hypothesized to be a cycle of progressive dysreg- ulation of the brain reward system that results in compulsive use and loss of control over drug taking and the initiation of behaviors associated with drug seeking (Koob et al. 1998; Koob and Le Moal 2001).
The view that addiction represents a pathological state of reward provides an approach to identifying the factors that contribute to vulnerability, addic- tion, and relapse in genetic animal models (Laakso et al. 2002).
Although each type of drug will be described in- dividually below, most drug addicts today consume more than one type of drug, i.e., they will take any drug that has an effect on the central nervous system (CNS): stimulants such as cocaine, amphetamines;
sedatives such as alcohol, codeine, morphine, bar-
biturates, benzodiazepines, etc.; and hallucinogens
such as lysergic acid diethylamide (LSD), mescaline
and numerous other substances (Geschwinde 1998;
Karch 2001). Substances used in substitution therapy such as methadone and dihydrocodeine (DHC) also have considerable toxic potential and drug addicts consume these substances in highly toxic doses. Par- ticularly the combination of these substances with other drugs − including alcohol − can be fatal.
Since in neuropathology only the final condition is assessed, in the individual case it is hardly pos- sible to differentiate which toxic substance caused which morphological changes. Animal studies are of little help in this regard since chronic abuse with such high dosages of toxic substances cannot be cre- ated even experimentally, as a rule. In addition the drug scene itself has an influence on the health of street users and can create secondary effects: intra- venous injection of suspensions containing insoluble particulate substances, for example, or infections caused by needle sharing, malnutrition, and/or the antisocial milieu together with immunodeficiencies secondary to drug consumption. HIV infection is an ever-present possibility.
In forensic-neuropathological practice, therefore, the morphological feature is usually a mixed sequela produced by numerous factors. Nevertheless, we will attempt to present the functional and pathological changes regarded as typical for each toxic agent.
19.2 Cannabis
Preparations from cannabis species have been used since antiquity, not only as psychotropic drugs but also in the treatment of a number of ailments. Over 60 cannabinoid compounds are present in hemp.
“Marijuana” is made from the tops and leaves of the hemp plant; “hash” from resins covering the flowers and leaves of female plants (Brust 1999). The main active component ∆
9-tetrahydrocannabinol (THC) produces most of its effects on the CNS by interact- ing with specific cannabinoid receptors on neurons (CB
1-receptors). Under normal circumstances, these receptors are thought to be one element of a neu- rotransmitter system that controls neuronal excit- ability. Other components of this putative signaling system include cannabinoids that are found natu- rally in the body, as well as cellular mechanisms by which these “endocannabinoids” are synthesized, transported, and metabolized (Piomelli et al. 2000 − for review see Christie and Vaughan 2001).
Cannabis has been considered an entry drug on the path to “hard” drugs and for this reason is pro- hibited by law in most Western countries. An inhaled dose of at least 2 mg and an oral dose of at least 10 mg THC is assumed to be the normal dosage. The target organ is the CNS.
Effect.
Marijuana and hash are smoked or consumed orally. After a few “hits,” the smoker feels relaxed and euphoric, his conscious processes and orienta- tion remaining largely unaffected. After even low or medium doses however a mild stupor can occur.
Among the psychophysical effects are impaired temporal and spatial orientation, cognitive abilities, vision, motor function (ataxia), and circulation. In acute intoxication, e.g., driving ability is impaired.
At the same time, there is a reduction in spontaneity and a certain apathy. At high doses, some individu- als experience illusions or hallucinations.
The “high” peaks after about 15−40 min (smok- ing) or 30−120 min (oral application), and lasts for up to 2−6 h. The half-life of THC in blood plasma is 1−4 days; in extreme cases, metabolites of THC can be demonstrated in blood for more than 10−20 days.
The urine of chronic users contains traces of canna- binoids (mainly the glucuronide of THC-COOH) for as long as 1−2 months.
After prolonged use, a certain psychic tolerance to THC can develop. It is still controversial whether chronic THC consumption can lead to mental ab- normalities (Weinrieb and O‘Brien 1993). The most often discussed abnormality is an “anti-motivated syndrome” characterized by apathy and flat affect, decreased attentiveness, and impaired short-term memory (Hollister 1967). Frequent cannabis use in teenage girls predicts later depression and anxiety, with daily users carrying the highest risk (Patton et al. 2002). Given recent increasing levels of cannabis use, measured reduction of frequent and heavy rec- reational use seems warranted. Moreover, evidence establishes a clear link between the use of cannabis and psychiatric illness, i.e., psychosis (Arseneault et al. 2002; Zammit et al. 2002). Recent studies have also found links between the use of marijuana and depression (Hall and Degenhardt 2000; McKay and Tennant 2000; Bovasso 2001; Rey et al. 2002).
Morphologically evident permanent injury of the CNS has not been described (Ray et al. 1979). THC may be powerfully neuroprotective, reducing isch- emic neuronal necrosis (Louw et al. 2000) in spite of an increase in brain temperature (Perron et al.
2001).
19.3
Hallucinogens and Entactogens
Hallucinogens are substances which are commonly
associated with hallucinosis. Entactogens are sub-
stances which generate a sense of “the touch with-
in,” i.e., a substance that affects individual physical
sensations of touch. Hallucinogens and entactogens
not only affect a person‘s emotional state − they can
also induce deep psychological changes. These com-
pounds include substances that can alter sensory impressions and/or lead partly to sensory hallucina- tions. Hollister (1967) describes the following com- mon features:
1. Changes in mood and perception dominate 2. Minimal memory or intellectual impairment 3. No association with stupor or excessive agitation 4. Minimal side-effects on the autonomic nervous
system
5. Craving and addiction do not occur
Chemically the following three groups of hallucino- gens can be differentiated:
1. Phenylalkylamines (mescaline) 2. Indole alkylamines (LSD)
3. Substituted amphetamines [3,4-methylenediox- methamphetamine (MDMA), 3,4-methylene- dioxyethamphetamine (MDEA) − without hallu- cinogenic, but entactogenic effects − cf. Thoma- sius 2000].
Deaths relating to these compounds are extremely rare compared to heroin-induced deaths. However, the danger exists that the number will increase in the foreseeable future due to the increasing use of these substances. In central Europe meanwhile the preferred drugs are synthetic agents such as MDMA and MDEA.
19.3.1 Mescaline
Mescaline is obtained from cacti native from south- western North America and from the peyote plant.
Mescaline was already being produced synthetically at the turn of the last century (1900). However, the main source of mescaline today is the peyote plant.
An oral dose exceeding 700 mg has a toxic effect on the liver. The hallucinatory effect occurs after metab- olism, i.e., after the mescaline has bound to endoge- nous proteins. The half-life of mescaline is about 6 h.
The highest concentrations occur in the liver and kidneys, the lowest in the brain, where after 30 min mescaline can no longer be detected. About 2% of the ingested mescaline penetrates the blood−brain barrier. The hallucinatory effect begins within 1−2 h and lasts for 8−12 h. In an accidental death attrib- uted to a mescaline-induced state of confusion, the following concentrations were found: blood 9.7 µg/l, urine 1,163 µg/l (Reynolds and Jindrich 1985). Mor- phological alterations of the brain are not known.
19.3.2
Lysergic Acid Diethylamide (LSD)
LSD was first synthesized in 1938 by Albert Hoff- mann. Today LSD is taken at “rave” parties as an alternative to MDMA, almost exclusively in small − non-toxic − doses. The resulting levels in urine range over 2−3 µg/l; i.e., near the limit of detection. How- ever, the metabolite’s levels (2-oxo-3-hydroxy-LSD) are comparably high. A single standard street dose today is 20−80 µg (Nelson and Foltz 1992). LSD has an estimated half-life of 2.5 h. Clinical symptoms are similar to those produced by mescaline. From 1960 to 1980, numerous cases of acute panic reactions, flashbacks, and homicides were described (Klepfisz and Racy 1973), but today these phenomena are no longer observed. Only a few deaths from LSD toxic- ity have been reported. No specific neuropathologi- cal features are known.
19.3.3
Amphetamine Substitutes
Amphetamine substitutes are summed up by the term “designer drugs” and are generally taken in tablet form (e.g., “ecstasy”), and are often used to enhance performance. The drugs have both amphet- amine-like and entactogenic properties. The main consumers of designer drugs are young people who want to make social contacts and dance through the night in discos. Eighty-one deaths related to taking ecstasy in people aged 15−24 years during the peri- od 1997−2000 in England and Wales were evaluated (Schifano et al. 2003). Results of toxicological exami- nation were made available in 75 cases; MDMA was present in 68 (91%), MDEA in 7 (9%), and opiates or opioids in 44 (59%) of these cases. In 26 (38%) cases, one or more drugs had been prescribed to the de- ceased patient. Those substances are neurotoxic by selective inhibition of monoamine oxidase A (MAO- A; Scorza et al. 1997), and by the induction of acute hypertension.
19.3.3.1
MDMA (3,4-methylenedioxmethamphetamine)
The half-life of MDMA (synonyms: MDM, Eve, Ecsta-
sy) is about 8 h. In dogs, the LD50 is 8−23 mg/kg, in
Rhesus monkeys 17−28 mg/kg, after intravenous ad-
ministration. Following oral intake of 50 mg, a con-
centration of 105 µg/l could be detected in the blood
of an adult man after 2 h. Blood levels had declined
to 5.1 µg/l at 24 h. MDMA can still be detected in the
blood after 3 days (Verebey et al. 1988). In cases of le-
thal intoxication, blood levels of up to 1,260 µg/l have
been observed (Bedford et al. 1992). The blood levels of living and dead users overlap. The clinical picture is characterized by hyperpyrexia, seizures, dissemi- nated intravascular coagulation, rhabdomyolysis, and renal failure. In isolated cases (for review see Balmelli et al. 2001) the intake of fluids after MDMA ingestion may lead to potentially fatal hypervolemic hypotonic hyponatremia with cerebral edema.
MDMA acts on the CNS by increasing the re- lease of serotonin and catecholamines and prevent- ing reuptake (Abbott and Concar 1992). Clinically, chronic users are liable to develop paranoid psy- choses (McGuire et al. 1994; McCann et al. 2000;
Ricaurte et al. 2002), seizures, stroke, and various neurocognitive deficits as a result of neurotoxic le- sions (Thomasius 2000). In animal experiments using non-human primates the cerebral serotonin terminals were selectively destroyed in neocortex, striatum and hippocampus, and axonal injury could be demonstrated (Insel et al. 1989; Ricaurte et al.
1992, 2000). As demonstrated in mice by Colado et al. (2001), production of specific radicals might be possible by MDMA metabolites reacting in turn with nitric ions.
Neuropathological findings in human beings, in contrast, have not been published. A recent study gives evidence of the immunohistochemical reac- tivity of nearly all neurons and axons of the cere- brum and cerebellum with antibodies to MDMA and MDEA − in two cases (DeLetter et al. 2003). The pathophysiological significance of this reaction pat- tern is still unknown and the diagnostic relevance has to be reexamined.
MDMA seems to have a selective neurotoxic ef- fect on the serotonergic system (Battaglia et al. 1988).
Neurochemical investigations and functional neu- roimaging studies in humans suggest alterations of central nervous functions after ecstasy use lasting weeks to months (Obrocki et al. 2001). Moreover, pathologic-anatomic evidence of hyperthermia, rhabdomyolysis, renal failure, and disseminated intravascular coagulation as well as hepatopathy including acute yellow hepatic dystrophy have been described (Campkin and Davies 1992).
19.3.3.2
MDEA (3,4-methylenedioxyethamphetamine) This drug is a close relative of MDMA (Synonym:
Eve, Ecstasy) with similar psychophysical and path- ological effects, kinetics, and concentrations. It is a true “designer drug” synthesized when MDMA was prohibited.
19.3.4 Other Agents
A large number of natural and synthetic hallucino- gens are known, e.g., psilocybin, 2,5-dimethoxy-4- methylamphetamine (DOM), and phencyclidine.
Neither acute nor chronic intoxication by most of these substances causes neuropathological changes.
Clinically and pathologically they are comparable in their effects to the aforementioned hallucinogens.
Phencyclidine (PCP), a dissociative anesthetic and widely abused psychotomimetic drug, and relat- ed agents (MK-801, tiletamine, and ketamine) have an apparent neurotoxic effect, which has heretofore been overlooked: these drugs induce acute patho- morphological changes in specific populations of brain neurons when administered subcutaneously to adult rats in relatively low doses (Olney et al. 1989).
It is unlikely, however, that similar lesions appear in the human brain.
19.4
Narcotics: Opium and Opioids
19.4.1
Basic Principles
19.4.1.1 Epidemiology
Most deaths due to chronic illicit drug abuse involve the consumption of opiates. The increase in the number of drug deaths in Europe and the USA is due mainly to the increase in the number of intravenous drug addicts. At present, the annual number of drug- related deaths is approximately 2,000 in Germany (Deutsches Bundeskriminalamt − cf. Oehmichen 1997) and 5,000 in the USA (Drug Abuse Warning Network). As there is no international agreement on the definition of a drug-induced death, the epidemi- ological data of different countries are not compara- ble. The German statistics include deaths classified according to the following criteria (Oehmichen and Staak 1988):
1. Direct toxic effect of the drug or its metabolites (accidental or suicidal overdose).
2. Direct toxic effect of adulterants or extraneous substances injected along with the drug.
3. Infections as a complication of the drug culture life-style including needle sharing or depressed immune function (Novick et al. 1989).
4. Death of a drug addict due to causes having no
direct connection with drug consumption.
19.4.1.2
Pathophysiology
The effective mechanism is explained by binding to specific opiate receptors on neurons of the CNS. Sev- eral different receptors have been described which are normally targeted by endogenous opioids (en- dorphins). The similarity in chemical structure of the exogenous morphine derivatives allows them to bind to (and possibly block) the neural receptors, thereby inhibiting, for example, the function of the endorphin system. This appears to hinder the release of acetylcholine and depolarization of the neurons (Dominiak 1992). At the same time, the effectiveness of dopamine is enhanced, since the propagation of inhibiting signals from neighboring neurons is also prevented. This leads to the typical phenomena of eu- phoria and addiction. The addiction itself is caused by the memory of the nerve cells for the positive re- inforcement of the experienced “high,” which is in turn due to the release of dopamine.
All narcotics have their target organ in the CNS, where they also inhibit the respiratory centers. An overdose causes a primary central respiratory arrest possibly with maintained heart action. The result is
massive congestion of blood in all organs secondary to the relative right ventricular insufficiency, which is aggravated by pharmacological paralysis of the vessels and by a hypoxia-induced reduction in vas- cular tone.
19.4.1.3 Neuropathology
In acute death resulting from heroin consumption, there is congestion, perivascular hemorrhages, and cerebral edema (Richter et al. 1973; Oehmichen et al.
1996). If an antidote is given (naloxone) or if artifi- cial respiration is performed, the patient can survive without any signs of neurotoxic injury.
Overdose victims with longer survival times, but who do not receive the above-mentioned therapies or whose therapy is applied too late, exhibit all the signs of generalized circulatory failure, i.e., corti- cal atrophy of the cerebrum (Fig. 19.1a) and the cer- ebellum (Fig. 19.1b). Sometimes there are patches of demyelination (Fig. 19.1c) producing a picture resembling that of the intermittent form of CO poi- soning (Sudo 1968). The sequelae will be a so-called ischemic encephalopathy (Makrigeorgi-Butera et al.
Fig. 19.1a−d. Ischemic encephalopathy in chronic drug addicts.
a Cerebral cortical atrophy in a 20-year-old man who survived an acute drug intoxication for <5 h. b Cerebellar atrophy; c bi-
lateral white matter softening as an indication of demyelination;
d bilateral pallidum necroses
1996; Oehmichen et al. 1996). Some cases additional- ly are characterized by a bilateral pallidum necrosis (Anderson and Skullerud 1999) (Fig. 19.1d) similar to that described in CO poisoning.
Chronic intravenous drug addicts, whose death is not caused by an acute overdose or late, unsuc- cessful resuscitation, almost always exhibit numer- ous secondary injuries caused by repeated phases of ischemia. In the brain, there is a focal increase of astrocytes and microglia (Fig. 19.2a, b), which is es- pecially conspicuous in the hippocampal formation and which is sometimes accompanied by selective
and segmental nerve loss in the CA1 region of the hippocampus (Ammon‘s horn) and in the Purkinje cell layer or in both areas (Oehmichen et al. 1996) (cf. Fig. 19.3). A total of about 26% of 162 fatal cases of drug abuse expressed a distinct neuronal loss in the cerebellar cortex (Purkinje cell layer) and in the CA1 region of the hippocampal area. The number of cases with reactive cortical changes, i.e., focal astro- cytic and/or microglial reaction, gave an indication of about 90% of dead chronic intravenous drug ad- dicts with relapsing transient ischemia (Oehmichen et al. 1996 − see Fig. 19.4).
In addition to these rather non-specific sequelae, some heroin addicts also show a transverse myelopa- thy (Stodieck 1983; Kishorekumar et al. 1985). This usually involves flaccid paralysis, which sometimes may be reversible. A morphological equivalent is present only in the rarest of cases: localized disten- tion of the cervical region of the spinal cord, as dem- onstrated by a myelogram − non-specific necroses of the gray matter or necrotizing vasculitis. The oc- currence of relapses after temporary withdrawal is striking, which some authors think points to an al- lergic pathogenesis.
A special form of injury is the occurrence of a leukoencephalopathy, usually observed in the white matter of the cerebrum and, occasionally, also in the cerebellum (Ropper and Blair 2003) (Fig. 19.1c). This is observed mainly following inhalation of heroin pyrolysate and is reported almost exclusively in Eu- rope (Poulet-Perez et al. 1992; Oehmichen et al. 1996;
Rizzuto et al. 1997). The pathological features are characterized by a more diffuse or spongiform de- myelination and patchy necrosis involving the globus pallidus and the cerebral and cerebellar hemispheric white matter. The putative pathogenetic mechanisms are anoxic damage to small vessels, cerebral edema, acidosis and edema, and severe hypoxic injury (see also Karch 2001).
In isolated cases, transverse myelitis has been de- scribed, but the incidence of this disorder seems to be decreasing (Karch 2001). The myelitis may be the result of a thromboembolic syndrome, an inflamma- tory vascular disease or a toxic manifestation due to some contaminants injected along with the heroin.
Moreover, peripheral neuropathy has been de- scribed associated with non-sterile injections, el- evated compartment pressure, or trauma (Sheehan and Jabre 1995). Occasional reports of stroke and polyarteritis-like disorders have been published.
Finally, it must be pointed out that some of the most common − and fatal − late complications seen in intravenous dope addicts are hepatitis B, C and HIV infections, which can be manifested in many different forms (pp. 593 ff).
The following are the most important narcotics.
Fig. 19.2a−c. Reactive alterations indicating a relapsing isch- emia. Focal increase of astrocytes (a) and microglia (b) in the hip- pocampal cortex; c loss of Purkinje cells and microglial activation (a GFAP; b, c CD68; magnification a ×300; b ×1,000; c ×500)
19.4.2 Morphine
Morphine is administered intravenously, subcutane- ously, orally, rectally, intranasally, and by inhalation.
Pure morphine is predominantly applied in clinical practice to treat pain.
The pharmacokinetics of morphine depends on the route of administration. Morphine is metabolized by conjugation with glucuronic acid to morphine-3- glucuronide (M3G) and morphine-6-glucuronide (M6G). The half-life of intravenous morphine is 1.7 h. The half-life of the glucuronide metabolites by contrast is 3.9±1.5 h for M3G and 2.6±0.69 h for M6G (Osborne et al. 1990).
It is striking that 6-acetylmorphine is present in the cerebrospinal fluid (CSF) and brain in much higher levels than in other organs (concentration − blood: 11.3 ng/ml; CSF: 58 ng/ml; brain: 158 ng/ml − Goldberger et al. 1994). The lethal dosage depends on individual tolerance.
The period of survival following the last mor- phine intake can be estimated based on the relation- ship between morphine levels in the cerebellum and medulla oblongata: cases with short survival times and acute deaths have higher concentrations in the cerebellum than in the medulla oblongata, whereas for cases with longer survival times the reverse is true (Vycudilik 1988).
19.4.3 Heroin
Heroin is produced synthetically. In the body, her- oin can be demonstrated for a maximum of 15 min and is metabolized into 6-monoacetylmorphine (6- MAM). This in turn is metabolized into morphine and finally to glucuronides (M3G and M6G).
The lethal dosage depends on individual tolerance and − in part − on the environmental circumstances.
While concentrations of free morphine in cases of le- thal overdose vary widely (from 50 µg/l to 1500 µg/
l), it is now assumed generally that blood levels be- low 100 µg/l are mostly survived, whereas levels ex- ceeding 100 µg/l are potentially lethal (Recker 1998;
Meissner et al. 2002). Fatalities at lower blood levels point to other factors contributing to the death: very low tolerance because of acute drug withdrawal, si- multaneous consumption of other drugs such as al- cohol, or dihydrocodeine, or accompanying illnesses such as respiratory infection (Koch 2002).
19.4.4 Codeine
Codeine is a naturally occurring alkaloid found in opium, which is metabolized to morphine. Its half- life is 2.4−3.2 h. The therapeutic dosage as an anti- tussive is 30−50 mg/day (maximum 100 mg/day).
Codeine has a slight sedative effect and is mildly analgesic. Codeine is used by drug addicts as a sub- stitute and during therapeutic withdrawal periods
Fig. 19.3a, b. Frequency of neuronal loss in chronic intravenous drug addicts is demon- strated in about 26% of 162 cases: a either in the cerebellar cortex or the hippocampal CA1 region or in both the areas (b) (cf. Oehmichen et al. 1996)
Fig. 19.4. Frequency of reactive alterations in the hippocampal area of chronic intravenous drug addicts (n=46) as an indication of a repeated ischemic state for a prolonged period which was demonstrable in 90% of the cases (cf. Oehmichen et al. 1996)
at doses of 300−400 mg/day, i.e., 5−10 capsules. The maximum effect is reached after 1−2 h, the effect lasts for 4−6 h. Chronic users develop tolerance.
Specific neuropathological alterations are not known.
19.4.5
Dihydrocodeine (DHC)
DHC is also an anti-tussive taken at doses ranging over 10−30 mg/day. The potential for addiction is somewhat greater than for codeine. This substance otherwise behaves like codeine.
19.4.6 Methadone
Methadone is synthetically produced.
D-Methadone is to be distinguished from the enantiomer
L-metha- done, levomethadone (
L-methadone = polamiden).
Since the early 1960s, methadone has been used in heroin withdrawal therapy in the USA. In Germany today
DL-methadone-HCl as well as Polamidon is ad- ministered orally in withdrawal therapy. The stan- dard single dose is 7.5 mg, the daily dose 30−50 mg, depending on the tolerance of the individual addict;
in some cases as much as 180−260 mg/day is needed to block the opiate receptors (Walton et al. 1978).
Numerous lethal methadone poisonings have been reported. Usually heroin and/or DHC is detected in addition to methadone. Fatal blood levels in cases of isolated lethal methadone poisoning range from 200 µg/l (Worm et al. 1993) to 1,000 µg/l (Worm et al. 1993) and 260−2,500 µg/l (Drummer et al. 1992).
Blood levels in methadone maintenance patients range 20−308 µg/l (Lorimer and Schmid 1992).
Under controlled oral intake of methadone and abstinence from all other drugs (when compliance is good), methadone therapy has a high success rate with a low risk of intoxication. In contrast, intrave- nous application of methadone in combination with heroin, barbiturates, amphetamines or alcohol en- tails a high risk of fatal intoxication.
19.4.7
Other Narcotic Agents
Other substances with effects similar to those of methadone are propoxyphene, fentanyl, and hydro- morphone. These substances are used much less of- ten and then only as substitute drugs.
19.5 Stimulants
19.5.1 Cocaine
Cocaine is obtained from the Bolivian coca plant. The ancient inhabitants of Bolivia knew of the narcotic effect of cocaine, and even today many of their de- scendants continue the habit of chewing coca leaves.
In Western populations, cocaine is taken mainly by snorting, smoking or intravenous injection.
Cocaine is said to increase the risk of homicide, suicide, and violent death in general. In fact, the ma- jority of cocaine-related deaths are a consequence of taking too much cocaine for too long (Karch 1999). In large American cities, most cocaine-related deaths (roughly 60%) are a direct consequence of chronic cocaine toxicity. Homicides account for an- other 20%. Suicide is the mode of death in <10% of cases where cocaine is detected, and in those cases the presence of cocaine, or cocaine metabolites, is usually an incidental finding (Tardiff et al. 1989).
Of course, isolated cases of suicidal overdoses have been reported (Sperry and Sweeney 1989), but most documented cases of massive overdose involve drug smugglers with a ruptured packet of cocaine in their intestines (Wetli and Mittelmann 1981).
Metabolism.
Cocaine has a half-life in humans of 0.5−1.5 h (Jatlow 1988). It is rapidly metabolized into ecgonine methyl ester (EME) and benzoylecgonine (BZE). Only a small percentage of cocaine is excreted unchanged in the urine (Ramcharitar et al. 1995).
Cocaine metabolites have a much longer half-life:
EME of about 4 h, BZE of almost 6 h after ingestion.
Because cocaine is more stable in the brain’s lipid-rich environment than in postmortem blood, brain cocaine levels are a better indication of levels at the time of death (Hernandez et al. 1994). Being lipophilic, cocaine easily crosses the blood−brain barrier, BZE only with difficulty (Misra et al. 1975).
The striatum has the highest density of cocaine re- ceptors in the brain. Cocaine levels in the brain are 4−10 times higher than those in plasma when mea- sured 0.5−2 h after administration of the drug (Spie- hler and Reed 1985; Benuck et al. 1989).
Pathophysiology.
Cocaine disrupts catecholamine
metabolism and prevents the reuptake of neu-
rotransmitters such as dopamine, noradrenaline,
adrenaline, and serotonin (White 1998). Additional
adrenaline is released from the adrenals (Knuepfer
and Branch 1992). Large doses of cocaine will result
in continuous seizure activity (Campbell 1988) and
affect temperature regulation (hyperthermia effect).
Increasing α-adrenergic stimulation of vascular smooth muscle causes vasoconstriction and isch- emia. Simultaneous stimulation of α- and β-recep- tors is associated with increased oxygen demand.
Robinson et al. (2001) could demonstrate that re- peated treatment with psychostimulant drugs, such as cocaine, amphetamine, or nicotine, produces long- lasting increases in dendritic branching and spine density in some brain regions (nucleus accumbens, pyramidal cells in the parietal cortex, hippocampus).
These changes may be related to the development of behavioral sensitization and the compulsive pattern of drug-seeking behavior (Kolb et al. 2003).
Pathology.
External markers of cocaine use may in- clude perforated nasal septum and crack keratitis.
Moreover, the histopathology is comparable with morphologic alterations in catecholamine intoxica- tion: contraction band necrosis of cardiomyocytes (Oehmichen et al. 1990; Karch 2001). Pulmonary edema is the principal finding at autopsy (Karch 1991). Although sudden death may be a fatal con- sequence of cocaine abuse, it is not sufficiently ex- plained pathophysiologically, even though numer- ous hypotheses exist (Karch 2001).
Neuropathology.
In only a few cases there were find- ings in the brain, especially cerebrovascular compli- cations (Levine et al. 1991): cerebral infarction as a consequence of vasoconstriction (Konzen et al. 1995), cerebral vasculitis with transmural infiltration by leukocytes and/or mononuclear inflammatory cells (Fredericks et al. 1991), subarachnoid and intracere- bral hemorrhages (Daras et al. 1994) (see also p. 573), seizures (Derlet and Albertson 1989; Brust 1993), and movement disorders (Brust 1993, Daras et al. 1994). In experimental toxicology an acute astroglial response (GFAP upregulation, increase of astrocytes, their cell size and shape complexity) could be demonstrated in mouse dentate gyrus (Fattore et al. 2002).
19.5.2
Cocaine Freebase: Crack
Mixing cocaine-hydrochloride with alkaline sub- stances such as sodium or ammonium bicarbonate or baking powder plus water produces the freebase of cocaine, the acute psychophysical effect of which exceeds even that of cocaine hydrochloride. Crack is usually smoked. When freebase cocaine is smoked, peak blood levels approach those obtained by intra- venous application and are rapidly attained. How- ever, the high lasts no longer than 30 min (Foltin et al. 1988; Foltin and Fischman 1991) and is followed by a phase of depression (“crash”), which the abuser often combats by renewed inhalation of crack.
The pathological findings correspond to the find- ings following cocaine abuse.
19.5.3
Amphetamine
and Methamphetamine (Speed)
These substances are produced synthetically. They are chemically related and produce similar effects.
Pharmacokinetics.
Both agents can be swallowed, in- jected, smoked or “snorted,” oral intake being most common. Orally applied
DL-methamphetamine has a mean plasma half-life of 11.1 h, peak levels being reached after about 3 h (Cook et al. 1992); the half- life after injection is 1.2 h. Up to 45% of metham- phetamine is excreted unchanged in the urine, 4−7%
is N-demethylated to form amphetamine.
Pathophysiology.
Both substances affect synapses by preventing the reuptake of catecholamines and they induce transmitter release. Blood levels do not correlate with the degree of impairment because of variations in tolerance. When measuring the levels of methamphetamine and those of its metabolite amphetamine in autopsied brain regions of human users, only slight regional differences were observed.
There is a heterogeneous distribution; no preferential retention in dopamine-rich brain areas was observed (Kalasinski et al. 2001). Moreover, methamphet- amine can induce neurotoxicity, which is associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis (for review see Davidson et al. 2001).
Clinical Correlation.
Functional brain disturbances give rise to, for example, psychotic symptoms, ap- parently caused by the affinity of amphetamines for sigma receptors (Itzhak and Stein 1990). Amphet- amine abuse can also cause personality changes, the abuser becoming restless, tense and fearful, partly paranoid, but not disoriented. Some abusers suffer auditory, tactile, and visual hallucinations.
These substances have a strong stimulating effect on the CNS. The peripheral sympathomimetic effects include vasoconstriction, elevated blood pressure, accelerated pulse and dilation of the upper airways as well as dryness of the mucous membranes of mouth and nose. Depending on dosage, mydriasis, hyper- tonia, tonicity of the smooth muscles and increased sexual drive also occur. Both agents are anorectics.
Users experience a subjective feeling of increased
powers of concentration and thinking and enhanced
self-confidence unaccompanied by an objective im-
provement in performance.
Pathology.
Methamphetamines (as well as MDMA and cocaine) apparently affect the temperature cen- ter in the brain stem: they are known to cause hy- perthermia (Käferstein and Sticht 2000), which can lead to rhabdomyolysis and renal failure and thus to death. Methamphetamines also damage the cardio- vascular system and chronic abuse can be fatal be- cause of a stimulant-related cardiomyopathy.
In the brain, amphetamine or methamphetamine in rare cases can cause hemorrhagic and ischemic strokes. About 50 cases have been described in the literature. Sometimes the cause is a necrotizing vas- culitis (Citron et al. 1970), sometimes preexisting ar- teriovenous malformations. In general, the hyperdy- namic circulation and increased cerebral blood flow with amphetamine (Berntman et al. 1978) can cause intracerebral hemorrhage (McGee et al 2004). Thus, although specific parenchymal patterns of brain de- generation have been described with different drugs in animal models (Ellison and Switzer 1993), it is as well to remember that most effects in humans are generalized, non-specific cardiovascular effects. Am- phetamine itself, however, may be toxic to dopamine terminals within the brain (Krasnova et al. 2001), and the cytokine interleukin-6 may play a role in meth- amphetamine neurotoxicity (Ladenheim et al. 2000).
Recent postmortem studies reported that chronic amphetamine users of unknown abuse intensity show long-term losses in dopamine and 5-hydroxy- tryptamine function in the caudate nucleus (most striking loss) and the putamen (Wilson et al. 1996).
19.5.4 Caffeine
Caffeine is the most widely used stimulant in the world. Numerous beverages and some medications are common sources of caffeine. Its spectrum of ef- fects, its toxicity, and its chemical structure all re- semble those of theophylline. A conspicuous finding in rat experiments is that, although both substances were present in nearly all tissues in about the same concentrations, the brain caffeine levels are about 25% higher than theophylline levels (Ståhle et al.
1992).
Pharmacokinetics.
In adults, the half-life of caffeine is 3−7.5 h, in infants it is much longer, being 82 h shortly after birth, and 14.4 h at age 3−4.5 months.
Effects.
Caffeine’s effects are dose dependent and vary widely at low doses. The effective mechanism involves inhibition of phosphodiesterase, exces- sive intake being accompanied by signs of sympa- thetic stimulation. Plasma catecholamine levels are thought to rise due to increased release of catechol- amine from the adrenal medulla (Benowitz et al.
1982). More recent studies, however, have cast doubt on these assumptions (Cameron et al. 1990). Caffeine has a direct effect on cardiac myocytes (increase of myocardial contractility and release of calcium ions from the sarcoplasmic reticulum), cerebral blood flow (which decreases), and on systolic blood pres- sure (which increases − Cameron et al. 1990).
Toxicity.
A few case reports have been published of high doses of caffeine (plasma levels 79−1,560 mg/l, cf. Mrvos et al. 1989) causing lethal cardiac arrhyth- mia together with pulmonary edema and visceral congestion. Specific morphological changes due to caffeine have not been described. Such changes may occur if caffeine is ingested together with some other β-antagonists, such as low doses of isoproterenol (myocardial necrosis).
The few published human autopsy reports de- scribe non-specific alterations at most. No specific lesions of the brain could be observed (Bryant 1981).
Animals studies show that caffeine augments hippo- campal necrosis due to electroshock seizures (Enns et al. 1996), but in ischemia acute and chronic effects of caffeine appear to differ, with acute caffeine aug- menting but chronic caffeine mitigating ischemic neuronal damage (Sutherland et al. 1991).
19.5.5 Ephedrine
Ephedrine is a natural product obtained from a spe- cies belonging to the genus “Ephedra” of the “Ephe- dracea” family. It is structurally similar to adrena- line and noradrenaline, but is chemically stable and effective when taken orally. Ephedrine produces an indirect sympathomimetic effect, which ranges be- tween that of adrenaline and noradrenaline. Ephed- rine releases noradrenaline from the storage gran- ules of the sympathetic nerve endings and inhibits the reuptake of noradrenaline from the synaptic gap.
Since ephedrine can pass the blood−brain barrier, it has a stimulating effect not only on the peripheral, but also on the central nervous system.
Chronic consumption can produce psychological dependence similar to that associated with amphet- amines. Exogenous psychoses (cerebral stimulant psychoses), which are accompanied by schizophre- nia-like symptoms and resemble alcoholic delirium, have also been described. Paranoid reactions pre- dominate.
19.5.6 Khat
Khat is used in East Africa and in Yemen as a psy-
chostimulant. When chewed, khat leads to activation
of the sympathetic nervous system, which in turn causes a rise in blood pressure, body temperature, and respiratory rate with variable effects on heart rate.
The early literature described cerebral hemor- rhages, myocardial ischemia, and pulmonary edema (Halbach 1972). Animal experiments have shown that khat releases dopamine and hinders uptake of dopamine.
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